title: Remifentanil has a minimal direct effect on sinoatrial node pacemaker activity in the Guinea pig heart.
abstract: BACKGROUND
  Whereas remifentanil administration is associated with severe bradycardia, it has yet to be fully investigated whether the negative chronotropic action of remifentanil is mediated by its direct action on sinoatrial (SA) node pacemaker activity in the heart versus indirect results of enhanced vagal activity.
  
  
  METHODS
  We examined the effects of remifentanil and fentanyl on the spontaneous action potentials of guinea pig SA node cells at concentrations of 5, 10, 100, and 1000 nM using the amphotericin B-perforated whole-cell patch-clamp technique. Isolated guinea pig hearts were perfused in a Langendorff mode with 5, 10, 100, and 1000 nM remifentanil.
  
  
  RESULTS
  The spontaneous firing rate and diastolic depolarization rate (DDR) of the SA node action potentials were 189.1 ± 14.8 /min and 74.1 ± 2.9 mV/s (n = 8), respectively, under control conditions, and were not significantly affected by exposure to 5 nM (P = 1.0 for both spontaneous firing rate and DDR; n = 6), 10 nM (P = 0.62 for spontaneous firing rate, P = 0.99 for DDR; n = 6), or 100 nM (P = 0.23 for spontaneous firing rate, P = 0.38 for DDR; n = 6) remifentanil. However, 1000 nM remifentanil modestly but significantly decreased the spontaneous firing rate (P = 0.0087) and DDR (P = 0.0072, n = 6). Remifentanil did not affect the heart rate of isolated Langendorff-perfused guinea pig hearts at concentrations of 5 nM (P = 0.98), 10 nM (P = 0.35), or 100 nM (P = 0.24) but significantly reduced the heart rate at 1000 nM (P < 0.0001). Fentanyl did not affect the spontaneous firing rate and DDR at concentrations of 5 nM (P = 1.0 for both spontaneous firing rate and DDR) and 10 nM (P = 0.62 for spontaneous firing rate, P = 0.79 for DDR), but it significantly reduced both at 100 nM (P = 0.00038 for spontaneous firing rate, P = 0.0080 for DDR) and 1000 nM (P < 0.0001 for both spontaneous firing rate and DDR).
  
  
  CONCLUSIONS
  Clinically relevant concentrations (nanomolar order concentrations) of remifentanil do not produce significant direct effects on intrinsic cardiac automaticity; thus, suggesting that remifentanil-induced bradycardia in the clinical setting is independent of its direct cardiac effects.
authors.affiliation: From the Departments of *Anesthesiology and †Physiology, Shiga University of Medical Science, Otsu, Shiga, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kojima
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Kitagawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsuura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Nosaka
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000666:Amphotericin B / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology*; D000077208:Remifentanil; D012849:Sinoatrial Node / Q000187:drug effects*
chemical_list: D000701:Analgesics, Opioid; D010880:Piperidines; D000666:Amphotericin B; D000077208:Remifentanil; D005283:Fentanyl